Considerable effort has been dedicated to understanding physiological and behavioral aspects of opioid dependence, yet little is known regarding how opioid dependence alters the reinforcing effects of heroin. Since 1968, when it was first demonstrated that prior dependence is not required for animals to initiate self-administration of abused drugs, very few studies have examined self-administration behavior in opioid-dependent subjects. The proposed research is designed to address questions of whether and how reinforcing effects of opioids are altered as a function of dependence, including dependence that results from identified pharmacotherapies for heroin addiction, e.g., buprenorphine. We have developed innovative self-administration procedures in which full dose-effect functions for the relative reinforcing strength of IV heroin can be rapidly determined. In these novel choice procedures, subjects learn to distribute their behavior throughout the session on the basis of the relative reinforcing strong features of an IV solution that is available for self-injection and an alternative reinforcer (food). These procedures are especially designed to divorce the reinforcing strength of drugs from other behavioral effects. In proposed studies, the self-administration of heroin and other opioid agonists will be determined under varying conditions of response cost to evaluate contextual influences on relative reinforcing strength. Next, studies will be conducted to determine how the relative reinforcing strength of heroin is modulated by acute treatment and chronic treatment with morphine-like drugs. Preliminary data indicate that the reinforcing strength of heroin in nondependent subjects can be predictably altered by treatment with other opioids or by changes in response cost, confirming the utility of these procedures for studies of the relative reinforcing strength of self-administered heroin. Following completion of these studies, alteration in the reinforcing strength of heroin will be gauged in relation to aspects of tolerance and dependence that develop during chronic treatment. Lastly, planned experiments will address the modification of heroin's reinforcing effects by nonopioid drugs, specifically GABA-A agonists. These studies are designed to empirically address questions raised by high rates of benzodiazepine abuse by opioid-addicted populations. Overall, the proposed studies will provide significant advances for evaluating contextual or pharmacological modifications of the reinforcing strength of heroin in nondependent and opioid-dependent individuals. Results of these studies will improve our ability to assess the effectiveness with which agonist-based medications may combat its addictive power.